Clinical and pharmacogenetic features of patients with upper gastrointestinal lesions at a multidisciplinary hospital: the role of nonsteroidal anti-inflammatory drugs.

OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications, but their use can be associated with a number of adverse reactions, including upper gastrointestinal lesions. The aim of the study was to identify clinical and pharmacogenetic factors associated with upper gastrointestinal lesions, including those linked to NSAIDs, in patients at a multidisciplinary hospital. METHODS: The study included 92 patients (mean age 59.4±16.5 years; 47 women), who underwent esophagogastroduodenoscopy during inpatient treatment. Patients' intake of NSAIDs and gastroprotectors during the year before hospitalization was considered. Demographic, clinical, laboratory data of patients were compared between groups, including genotyping for CYP2C9*2 rs179985, CYP2C9*3 rs1057910, CYP2C8*3 rs11572080, CYP2C8*3 rs10509681, PTGS-1 rs10306135, PTGS-1 rs12353214, and PTGS-2 rs20417 using real-time PCR. RESULTS: In NSAIDs+ patients, PTGS1 rs10306135 AT+TT genotypes increased the chance of developing gastrointestinal complications by 5.4 times (95 % CI=1.30-22.27). In total sample, smoking (OR=3.12, 95 % CI=1.15-8.46), and alcohol intake (OR=4.09, 95 % CI=1.05-15.87) increased odds of gastrointestinal damage. In NSAIDs+ patients omeprazole, famotidine and both famotidine and omeprazole during the last year were as ineffective as not taking gastroprotectors; in total sample famotidine (OR=0.19, 95 % CI=0.04-0.93) and two gastroprotectors (OR=0.13, 95 % CI=0.02-0.75) reduced the chance of upper gastrointestinal lesions. CONCLUSIONS: Pharmacogenetic features of patients may significantly contribute to the development NSAIDs-induced upper gastrointestinal injuries.

Pharmacogenetic markers of development of angioneurotic edema as a secondary side effect to enalapril in patients with essential arterial hypertension.

BACKGROUND: Angioneurotic edema is the most dangerous complication in angiotensin-converting enzyme inhibitors (ACEIs) therapy. Based on the current data, the clinical and genetic predictors of angioedema development are still understudied, which demonstrates the relevance of this study. OBJECTIVE: To reveal the pharmacogenetic predictors of the angioedema as a secondary side effect to enalapril in patients with essential arterial hypertension. METHODS: The study enrolled 111 subjects randomized into two groups: study group, patients with the angioedema as a secondary side effect to enalapril; and control group, patients without adverse drug reaction. All patients underwent pharmacogenetic testing. RESULTS: An association between the development of the angioneurotic edema and the genotypes AA rs2306283 of gene SLCO1B1, TT rs4459610 of gene ACE, and CC rs1799722 of gene BDKRB2 in patients was revealed. CONCLUSION: The findings justify further investigations of the revealed genetic predictors of angioedema with larger-size patient populations.

Effects of CYP2D6 allelic variants on therapy with tamsulosin in patients with benign prostatic hyperplasia.

OBJECTIVES: Tamsulosin is a first-line drug for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Despite its high ratings for efficacy and safety, these parameters may vary due to genetic polymorphisms of CYP2D6 enzyme, which is involved in the metabolism of the drug. This variability may have great impact on the therapy of LUTS associated with BPH and may require an individualized approach to drug selection. The aim of the study was to assess the impact of genetic polymorphisms in CYP2D6 on the efficacy and safety of tamsulosin therapy in patients with LUTS associated with BPH. METHODS: The study included 106 patients with LUTS/BPH (N40 according to ICD-10). All patients received monotherapy with tamsulosin 0.4 mg/day for at least 8 weeks. Depending on the severity of symptoms, all patients were divided into 2 groups based on the IPSS score: the first group of patients had moderate symptoms (n=57), and the second group of patients had severe symptoms (n=49). The results of treatment were assessed using the IPSS questionnaire with determination of quality of life (QoL), transrectal ultrasound of the prostate with determination of prostate volume and postvoid residual urine volume, and uroflowmetry. The carriage of allelic variants of CYP2D6 (*3, *4, *9, *10, and *41) were determined by polymerase chain reaction in all patients. RESULTS: In patients with moderate symptoms who was classified as «intermediate¼ metabolizers by CYP2D6, a statistically significant greater reduction in symptoms according to the overall IPSS scale at 8 weeks (p=0.046) and the obstructive symptom subscale starting from 4 weeks of treatment (p<0.05) was shown. Allelic variants of the CYP2D6 gene did not affect the frequency of adverse reactions to tamsulosin. CONCLUSIONS: The results of the study show that in patients with moderate LUTS associated with BPH who are «intermediate¼ metabolizers by CYP2D6, there is a better therapeutic effect of tamsulosin.

Genetic markers associated with adverse reactions of radioiodine therapy in thyroid cancer patients.

OBJECTIVES: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. METHODS: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. RESULTS: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. CONCLUSIONS: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

Genetic markers associated with adverse reactions of radioiodine therapy in thyroid cancer patients.

OBJECTIVES: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. METHODS: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. RESULTS: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. CONCLUSIONS: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

Pharmacogenetic predictors of development of secondary to enalapril dry cough in hypertensive patients.

OBJECTIVES: Development of the secondary to ACEI cough leads to discontinuation of the drugs of this group. Assessing the safety of the ACEIs with further development of customized approaches for their administration is a major scientific and practical problem. The objective of this study was to assess the association of the genetic markers with the development of the adverse drug reaction in the form of secondary to enalapril dry cough in the patients with essential arterial hypertension. METHODS: Study involved 113 patients with the secondary to enalapril cough and 104 patients without development of the secondary to enalapril adverse drug reaction. RESULTS: The patients carriers of the genotype AA rs2306283 of gene SLCO1B1 had 2-fold higher odds of developing the dry cough than those with the genotypes AG and GG (ОR=2.01, 95%CI=1.10-3.66, р=0.023). Similarly, the patients heterozygous for rs8176746 of gene АВО had 2.3-fold higher odds of developing the ADR in the form of dry cough than the carriers of the genotypes GG and TT (ОR=2.30, 95%CI=1.24-4.29, р=0.008). CONCLUSIONS: Statistically significant association between the development of the ADR in the form of secondary to enalapril dry cough and polymorphisms rs2306283 of gene SLCO1B1 and rs8176746 of gene ABO was revealed.

Association of CYP2C19 Polymorphic Markers with Cardiovascular Disease Risk Factors in Gas Industry Workers Undergoing Periodic Medical Examinations.

INTRODUCTION: Human cytochrome P450 (CYP) enzymes have a wide range of endogenous substrates and play a crucial role in cardiovascular physiology as well as in metabolic processes, so the issue of cytochrome P450 genes investigation has received considerable critical attention in the prevention of cardiovascular diseases (CVDs). AIM: Comprehensive assessment of relationship between CYP2C19*2, CYP2C19*3 polymorphisms and CVD risk factors in gas industry workers undergoing periodic medical examination (PME). MATERIALS AND METHODS: The study included 193 gas industry workers aged 30-55 years without acute diseases as well as exacerbations of chronic diseases, diabetes mellitus, and CVD history. CYP2C19 (rs4244285 and rs4986893) genotyping and analysis of the relationship between CYP2C19*2 and CYP2C19*3 and CVD risk factors were performed. RESULTS: The CYP2C19*2 (A) and CYP2C19*3 (A) loss-of-function alleles frequencies were 20% and 2%, respectively. The frequency of high-normal blood pressure (BP) (130-139 and/or 85-89 mm Hg) detection was higher in the CYP2C19*2 (A) subgroup compared with wild-type GG allele carriers (26.7% vs. 5.2%, p = 0.03) in individuals without arterial hypertension (AH) and BP ≥ 140 and/or 90 mm Hg on PME. The median systolic BP levels were 5 mm Hg higher in CYP2C19*2 (A) group than in CYP2C19*2 (GG) group (125 vs. 120 mm Hg, p = 0.01). There was a similar trend for diastolic BP (85 vs. 80 mmHg, p = 0.08). CYP2C19*2 (A) was associated with higher mean levels of both systolic and diastolic BP (p = 0.015 and p = 0.044, respectively) in patients with AH. CYP2C19*2 was not associated with the other CVD risk factors analyzed. CONCLUSION: The association of CYP2C19*2 with BP level suggests a possible role of this factor in AH development, which requires further research.

Effect of CYP2C9, PTGS-1 and PTGS-2 gene polymorphisms on the efficiency and safety of postoperative analgesia with ketoprofen.

OBJECTIVES: Patients undergoing cardiac surgery develop post-sternotomy pain syndrome. The aim of this study was evaluation of the influence of CYP2C9, PTGS-1 and PTGS-2 genes polymorphisms on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery. METHODS: The study included 90 patients undergoing cardiac surgery. A real-time polymerase chain reaction was used for the detection of single nucleotide polymorphisms (SNP). Pain intensity was measured by the Numeric Rating Scale (NRS). Dyspeptic symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS). Acute kidney injury (AKI) was determined by Kidney Disease Improving Global Outcomes criteria. RESULTS: Pain intensity by the NRS score was significantly higher in patients with CYP2C9*3 АA genotype compared to АC genotype: 7 [1,10] and 6 [2,7] (p=0.003); 7 [1,10] and 6 [2,7] (p=0.04); 6 [0; 10] and 5 [2,6] (p=0.04); 5 [0; 8] and 3 [0; 8] (p=0.02), on days 1, 2, 3 and 5 in the postoperative period, respectively. GSRS score was higher in patients with CYP2C9*2 CT genotype compared to CС genotype: 19 [15; 42] and 18 [15,36] (p=0.04), respectively. There were no significant differences in the pain intensity, dyspepsia severity and AKI frequency in patients with homozygous and heterozygous genotypes for PTGS-1 rs10306135, PTGS-1 rs12353214, PTGS-2 rs20417. CONCLUSIONS: CYP2C9*3 and CYP2C9*2 gene polymorphisms may affect efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.

Clinically relevant pharmacogenetic markers in Tatars and Balkars.

This study was aimed to investigate the prevalence of CYP2C9*2 (p.430C > T, rs1799853), CYP2C9*3 (p.1075A > C, rs1057910), CYP4F2*3 (p.1297G > A, rs2108622), CYP2C19*2 (p.681G > A, rs4244285), CYP2C19*3 (p.636G > A, rs4986893), CYP2C19*17 (p.1260C > A, rs12248560), ABCB1 (p.3435C > T, rs1045642), CYP2D6*4 (p.1846G > A, rs3892097), SLCO1B1*5 (p.521T > C, rs4149056) and CES1 (p.1168-33A > C, rs2244613) among Tatars and Balkars ethnic groups living in Russia to provide a basis for future clinical studies concerning on understanding of population-level differences in drug response. The study involved 341 apparently healthy, unrelated, and chronic medication-free volunteers of both sexes of ethnic groups of Tatars and Balkars living in Volga and Caucasus regions of Russia. Genotyping was performed using real-time polymerase chain reaction-based methods. The allelic prevalence of studied markers in ethnic groups were compared with Russians as a largest ethnic group in Russia. Statistically significant differences for the following gene polymorphisms were found between both ethnic groups in respect of different markers and with Russians. Our study shows differences in prevalence of the main relevant pharmacogenetic markers in Tatars and Balkars. These findings should be taken into consideration for personalization algorithms development and pharmacogenetics implementation in regions with ethnic minorities as Russia has.

An improved extraction protocol for therapeutic dabigatran monitoring using HPLC-MS/MS.

A new sample extraction protocol was developed for pharmacokinetic studies of dabigatran with high-performance liquid chromatography separation - electrospray ionization time-of-flight mass spectrometry analysis. After protein precipitation with acetonitrile, free dabigatran and its metabolites are separated into water phase by water-dichloromethane liquid-liquid extraction to purify the sample from proteins and endogenous lipophilic compounds. Chromatographic separation was achieved on an Agilent Zorbax SB-CN column (150 × 4.6 mm, 5 µm)) using 0.1% aqueous solution of formic acid and acetonitrile (80:20) as the mobile phase. Agilent Zorbax SB-CN column was selected to improve sample resolution and to avoided early elution of dabigatran previously seen when using a C18 column. The extended calibration curve was constructed from 5 to 1000 ng/L while precision and accuracy were assessed at four levels across the linear dynamic ranges. Within-run precision was <5.6% and the between-run precision was <3.9%. The method accuracy ranged from 89.8% to 104.4%. The developed method was successfully applied to 30 patient samples to evaluate antithrombotic efficacy and anticoagulant activity of dabigatran following knee endoprosthesis surgery.

Effect of CYP3A4, CYP3A5, ABCB1 Gene Polymorphisms on Rivaroxaban Pharmacokinetics in Patients Undergoing Total Hip and Knee Replacement Surgery.

INTRODUCTION: Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis. AIM: Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery. METHODS: The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated. RESULTS: The study revealed the following haplotypes: (1) ABCB1 rs1045642-CYP3A4 rs35599367 and (2) ABCB1 rs4148738-CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001). CONCLUSION: No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.

Genetic Polymorphisms of Cytochrome P450 Enzymes and Transport Proteins in a Russian Population and Three Ethnic Groups of Dagestan.

AIM: The objective of this study was to investigate the prevalence of polymorphic markers of the CYP2C19, CYP2C9, CYP2D6, SLCO1B1, and ABCB1 genes among the three ethnic groups in Dagestan and compare it with the carrier frequency of these markers among the Russian population living in Moscow. METHODS: The study involved 186 healthy, unrelated, and chronic medication-free volunteers (53 males and 133 females) of the three ethnic groups in the Dagestan Republic: 46 Laks, 90 Avars, and 50 Dargins. Genotyping was performed using real-time polymerase chain reaction-based methods. The allelic prevalences of the three Dagestan peoples were compared with ethnic Russians from the Moscow region. RESULTS: Statistically significant differences for the following gene polymorphisms: CYP2C19*17, CYP2C9*3, ABCB1 (C3435T), SLCO1B1*5 were found between the Russian population and the three ethnic groups of the Dagestan republic. CONCLUSION: The data obtained from this study will help with prioritization genotyping in the region.